An increasing number of studies in humans and rodents demonstrate that the abnormal intrauterine metabolic milieu associated with obesity in pregnancy can have long-lasting effects on the development of obesity and diabetes in offspring. Both human and animal studies show that maternal obesity significantly increases fetal and neonatal adiposity and that offspring of obese mothers have a very high risk of developing obesity in later life. We have found that offspring of female rats fed a cafeteria diet either prior to pregnancy, or prior to and during pregnancy have increased fat mass and insulin resistance at 2 weeks of age compared to offspring of dams fed ordinary rat chow (preliminary data). Fat mass is also increased in pups of rat chow fed dams that are cross-fostered to an obese dam. However, the increase in fat mass of cross-fostered pups is not as great as in pups that were exposed to maternal obesity during pregnancy, suggesting that prenatal exposures may be more important than postnatal exposure in programming obesity in the offspring. The mechanisms linking maternal obesity to the later development of obesity in the offspring are unknown. Maternal obesity results in increased plasma levels of saturated fatty acids and decreased levels of long-chain polyunsaturated fatty acids (PUFAs). This abnormal fatty acid profile causes oxidative stress and inflammation. Therefore, these findings and our previous studies lead us to hypothesize that in maternal obesity, oxidative stress induces epigenetic modifications of key adipogenic genes in the embryo thereby potentiating the adipocyte differentiation program by enhancing lineage commitment as well as terminal differentiation in the offspring. We will test these hypotheses by the following specific aims: Specific Aim 1: Determine whether the pre-implantation stage of development represents the critical window of susceptibility to the effects of maternal obesity. Specific Aim 2: Demonstrate that maternal obesity potentiates adipogenesis in the offspring. Specific Aim 3: Determine the mechanisms by which epigenetic modifications increase expression of adipogenic genes. Specific Aim 4: Demonstrate that oxidative stress causes obesity in the offspring of the obese dam. PUBLIC HEALTH RELEVANCE: Maternal obesity significantly increases fetal and neonatal adiposity and offspring of obese mothers have a very high risk of developing obesity in later life. This application will address the mechanisms underlying this phenomenon and determine if a diet enriched with antioxidants will prevent the development of obesity in the offspring. Since the incidence of obesity is rapidly increasing in the United States, these studies will have great impact on health.